The prevailing research paradigm in bone biology is that differentiation and functions of the two bone-specific cell types, osteoblasts and osteoclasts, are determined by secreted molecules that can either be cytokines acting locally, or hormones acting systemically (Harada and Rodan, 2003; Takayanagi, 2006; Teitelbaum and Ross, 2003). Applicants have discovered a previously unknown genetic pathway occurring in osteoblasts in which decreased activity of OST-PTP leads to decreased activity of gamma-carboxylase, which in turn leads to increased secretion of undercarboxylated/uncarboxylated osteocalcin from the osteoblasts, with beneficial effects on glucose homeostasis.
OST-PTP is the protein encoded by the Esp gene. The Esp gene was originally named for embryonic stem (ES) cell phosphatase and it has also been called the Ptprv gene in mice. (Lee et al, 1996, Mech Dev 59: 153-164). OST-PTP is a receptor-like protein osteotesticular protein tyrosine phosphatase as well as fragments and variants thereof. OST-PTP is a large, 1711 amino-acid long protein that includes three distinct domains. OST-PTP has a 1068 amino-acid long extracellular domain containing multiple fibronectin type III repeats.
Esp expression is restricted to ES cells, the gonads and the skeleton. In the gonads, Esp is specifically expressed in Sertoli cells of the testis and coelomic epithelial cells of the ovaries. During development, Esp is initially expressed in the apical ectodermal ridge of the limbs. Later during embryonic development and after birth, its expression becomes restricted to pre-osteoblasts and osteoblasts (i.e., Runx2-positive cells) of the perichondrium and periosteum. Because of its bone and testicular localization, the gene product of Esp is often referred to as osteoblast testicular protein tyrosine phosphatase (OST-PTP).
Osteocalcin, one of the very few osteoblast-specific proteins, has several features of a hormone. Ducy et. al. demonstrated that mineralized bone from aging osteocalcin-deficient mice was two times thicker than that of wild-type. It was shown that the absence of osteocalcin led to an increase in bone formation without impairing bone resorption and did not affect mineralization. Multiple immunoreactive forms of human osteocalcin have been discovered in circulation (Garnero et al. J Bone Miner Res 1994; 9:255-4) and also in urine (Taylor et al. J. Clin. Endocrin. Metab. 1990; 70:467-72). Fragments of human osteocalcin can be produced either during osteoclastic degradation of bone matrix or as the result of the catabolic breakdown of the circulating protein after synthesis by osteoblasts.
The experiments described herein provide the first evidence that the skeleton is an endocrine regulator of energy metabolism and thereby determines, in part, the onset and severity of metabolic syndrome or type 2 diabetes, as well as the risk of developing these disorders. The experiments described herein particularly establish that the skeleton makes and secretes undercarboxylated osteocalcin which acts as a hormone regulating energy metabolism. Described herein is a previously unknown genetic pathway occurring in osteoblasts in which decreased activity of OST-PTP leads to decreased activity of gamma-carboxylase, which in turn leads to increased secretion of undercarboxylated osteocalcin from the osteoblasts, with beneficial effects on glucose homeostasis.